The influenza virus belongs to the Orthomyxoviridae family and is a negative-sense. RNA virus with a segmented, single-stranded genome. Influenza is a viral disease spread initially from avian species and mutating into mammalian-infectious strains. The disease generally causes body aches, coughing, sneezing, fatigue, fever, headache, nausea, vomiting, and irritated eyes, skin, throat, and nose. The World Health Organization (WHO) estimates that 3 to 5 million people are infected each year, and as many as 500,000 people die from the complications of influenza infections in non-epidemic years and millions in epidemic years. The Center for Disease Control has found an average 5% to 20% of the U.S. population contracts influenze, with over 200,000 U.S. residents hospitalized and about 36,000 people dying from flu. Additional information provided by the WHO documents three influenza pandemics that occurred within the past century. The deadliest outbreak ever recorded (1918-19) killed about 40 million people worldwide, including about 650,000 in the United States. The economic impact caused by influenza due to decreased productivity and increased health care utilization is in the billions of dollars.
The viral nucleocapside is covered by a cell-derived envelop that contains three surface proteins: A trimeric hemagglutinin, and the tetrameric proteins Neuraminidase and M2. Two classes of antiviral drugs are currently in use in many countries around the world. The M2 ion channel blockers amantadine and rimantadine have been in use for a long time (Hall, M. and M. D. Brown. 2005. Evidence-based emergency medicine/systematic review abstract. Are amantadine and rimantadine effective in healthy adults with acute influenza? Ann. Emerg. Med. 46:292-293), however they are not well tolerated (Keyser, L. A., et al. 2000. Comparison of central nervous system adverse effects of amantadine and rimantadine used as sequential prophylaxis of influenza A in elderly nursing home patients. Arch. Intern. Med. 160:1485-1488; Stange, K. C., D. W. Little, and B. Blatnik. 1991.

Adverse reactions to amantadine prophylaxis of influenza in a retirement home. J Am. Geriatr. Soc. 39:700-705) and ineffective against the avian H5N1 virus. Neuraminidase-inhibitors (e.g. oseltamivir and zanamivir) are the only FDA-approved drugs available capable of reducing the risk of dying from H5N1 infection; however, the isolation of strains resistant to oseltamivir (Chotpitayasunondh, T. K. et al. 2005. Human disease from influenza A (H5N1), Thailand, 2004. Emerg. Infect. Dis. 11:201-209), and possible link to the appearance of neurological side-effects, emphasize the need for additional anti-influenza drugs. Ribavirin is a nucleoside mimetic anti-viral drug against DNA and RNA viruses, which interferes with duplication of viral genetic material. Ribavirin is approved only for use against chronic hepatitis C with hepatic damage in the United States, though Ribavirin exhibits an effect against influenza and is sold outside the U.S. as an anti-influenza medication.

The appearance of drug-resistant isolates to adamantine (Bright, R. A., et al. 2005. Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern. Lancet 366:1175-1181; Bright, R. A., et al. 2006. Adamantane resistance among influenza A viruses isolated early during the 2005-2006 influenza season in the United States. JAMA 295:891-894) and neuraminidase inhibitors (Nicholson, K. G., et al. 2003. Influenza. The Lancet 362:1733-1745; Yen, H. L., et al. 2005. Neuraminidase Inhibitor-Resistant Influenza Viruses May Differ Substantially in Fitness and Transmissibility. Antimicrob. Agents Chemother. 49:4075-4084) further justifies the need to identify novel compounds with antiviral activity against influenza. Currently, scientists fear that the new avian influenza H5N1 could mutate into a strain that easily transmits from person to person, sparking a human influenza pandemic resulting in devastating human and economic consequences. Preparedness for a coming pandemic will require development of new vaccines and antiviral therapeutics. According to the WHO, since the initial outbreak in South East Asia in 1997 until Nov. 13th 2006, the H5N1 virus has thus far spread to at least ten countries and caused the death of 153 people and the mandatory slaughtering of millions of birds.